Two researchers in a leading gene therapy lab committed scientific misconduct and have been dismissed, Mount Sinai School of Medicine announced this afternoon. But an investigation into the matter yielded no evidence of misconduct by the lab’s lead scientist, Savio Woo.
That investigation, which also led to the retraction of four journal articles, began after Woo alerted the institution’s research integrity office that he suspected two postdocs in his lab of misconduct. Mount Sinai has not officially released the names of the postdocs, but the results of the inquiry were reported to “the appropriate government agencies”, according to a statement released by the medical school. (It is common practice to report research misconduct findings to government funding agencies.)
Woo is perhaps best known for his work on a rare genetic disease called phenylketonuria (PKU). In 1983, Woo cloned the gene that is mutated in PKU patients, opening the door to developing gene therapy treatments for the disease. He then went on to pioneer gene therapy techniques that showed promise, in mice, for treating PKU and other conditions, including cancer. “He’s definitely had a huge presence in the field for many, many years,” says Cary Harding, who studies PKU at Oregon Health & Science University in Portland, Oregon.
The four retractions were first highlighted this Wednesday by the blog Retraction Watch. The reason for the retraction is clear for two of the publications: the same micrograph was used for a figure in both a 2009 Human Gene Therapy and a 2008 Journal of the National Cancer Institute article. The two publications evaluated the use of the bacterium Clostridium perfringens to target tumours. “All co-authors have requested a retraction…and sincerely apologize to their colleagues,” one of the letters states.
Woo did not respond to requests for comment. James Wetmur, a microbiologist at Mount Sinai and a coauthor on the two papers, says the studies’ authors had been advised by Mount Sinai’s legal office not to discuss the matter.
Meanwhile, retractions of the remaining two papers – another in Human Gene Therapy and one in Proceedings of the National Academy of Sciences USA – merely cite “data irregularities”, an ambiguous description that leaves researchers in the field guessing. “It’s hard to tell from the retraction what’s going on,” says Harding. “Was it only part of the paper or did the whole thing fall apart?”
Both of these papers describe a method that can shuttle genes into the mouse genome without relying on viruses. In the PNAS article, the technique was used to cure mice of PKU. The papers were authored by Woo and his postdoc, Li Chen, but the retractions were requested by Woo alone. “After re-examining the laboratory records, I have concluded that there are data irregularities underlying this paper that warrant its retraction. I regret not recognizing these irregularities before the manuscript was published and apologize for any inconvenience this might have caused,” Woo wrote.
Yuet Wai Kan of the University of San Francisco edited the PNAS paper and says that Woo later told him that the data in that paper could not be reproduced. Kan did not know specifically which data were problematic.
Several follow-up papers, including two 2007 Molecular Therapy papers (here and here), appear to directly build on the PNAS study. They have not yet been retracted, and it is not clear whether those data are also in question. If the papers are not retracted, it would seem to suggest that the core conclusions of the PNAS study, that the method Woo and Chen reported for introducing genes can be used to treat PKU in mice, are correct.
Ultimately, it is unclear how much of an impact the retractions will have on the field. Harding says the PNAS paper generated excitement because researchers are eager to find new methods of shuttling genes into genomes without using viruses, which raise safety concerns. The paper, which was published in 2005, has been cited 32 times. When Harding first read the article, he was immediately impressed by how robust the work seemed. “I was pretty convinced by the data,” he says.
Nevertheless, he says, it was difficult to imagine translating the technique into the clinic. Woo’s study relied on a technique called ‘hydrodynamic injection’, which involves injecting a very large volume of fluid containing the therapeutic DNA over a short period of time. The technique works in mice, but may not be amenable to humans, Harding says.
Furthermore, some have found that a similar gene-shuttling system causes potentially dangerous deletions and even chromosomal rearrangements in the host genome. Those findings are controversial, but would likely raise safety concerns about trying the technique in humans, says Beat Thöny, who studies metabolic diseases at the University of Zurich. And Kan says that when his own lab was looking for a virus-free method of introducing genes into cells, they opted for a different technique that could be used with a commercially available kit.
Image: Mount Sinai Medical Center